title: A novel herbal formula induces cell cycle arrest and apoptosis in association with suppressing the PI3K/AKT pathway in human lung cancer A549 cells.
abstract: OBJECTIVE
  In recent years, the incidence of lung cancer, as well as the mortality rate from this disease, has increased. Moreover, because of acquired drug resistance and adverse side effects, the effectiveness of current therapeutics used for the treatment of lung cancer has decreased significantly. Chinese medicine has been shown to have significant antitumor effects and is increasingly being used for the treatment of cancer. However, as the mechanisms of action for many Chinese medicines are undefined, the application of Chinese medicine for the treatment of cancer is limited. The formula tested has been used clinically by the China National Traditional Chinese Medicine Master, Professor Zhonging Zhou for treatment of cancer. In this article, we examine the efficacy of Ke formula in the treatment of non-small cell lung cancer and elucidate its mechanism of action.
  
  
  METHODS
  A Balb/c nude mouse xenograft model using A549 cells was previously established. The mice were randomly divided into normal, mock, Ke, cisplatin (DDP), and co-formulated (Ke + DDP) groups. After 15 days of drug administration, the animals were sacrificed, body weight and tumor volume were recorded, and the tumor-inhibiting rate was calculated. A cancer pathway finder polymerase chain reaction array was used to monitor the expression of 88 genes in tumor tissue samples. The potential antiproliferation mechanism was also investigated by Western blot analysis.
  
  
  RESULTS
  Ke formula minimized chemotherapy-related weight loss in tumor-bearing mice without exhibiting distinct toxicity. Ke formula also inhibited tumor growth, which was associated with the downregulation of genes in the PI3K/AKT, MAPK, and WNT/β-catenin pathways. The results from Western blot analyses further indicated that Ke blocked the cell cycle progression at the G1/S phase and induced apoptosis mainly via the PI3K/AKT pathway.
  
  
  CONCLUSIONS
  Ke formula inhibits tumor growth in an A549 xenograft mouse model with no obvious side effects. Moreover, Ke exhibits synergistic antitumor effects when combined with DDP. The mechanism of action of Ke is to induce cell cycle arrest and apoptosis by suppressing the PI3K/AKT pathway. Further research will be required to determine the mechanism of action behind the synergistic effect of Ke and DDP.
authors.affiliation: Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xiong
authors.forename: Miao
authors.initials: M
authors.lastname: Jiang
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Huang
authors.forename: Meijuan
authors.initials: M
authors.lastname: Chen
authors.forename: Kejun
authors.initials: K
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Lian
authors.initials: L
authors.lastname: Yin
authors.forename: Yuping
authors.initials: Y
authors.lastname: Tang
authors.forename: Mingyan
authors.initials: M
authors.lastname: Wang
authors.forename: Lihong
authors.initials: L
authors.lastname: Ye
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhan
authors.forename: Jinao
authors.initials: J
authors.lastname: Duan
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D029001:Herbal Medicine / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000081082:Phosphoinositide-3 Kinase Inhibitors; D028321:Plant Preparations / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D028321:Plant Preparations; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin
keywords: PI3K/AKT pathway; Zhou’s formula of Ke Jin Yan; apoptosis; cell cycle; cisplatin; non–small cell lung cancer